Shining a light on how neuroscientists can control our brains

In 1999, neuroscientist Gero Miesenböck dreamed of using light to expose the brain's inner workings. Two years later, he invented optogenetics, a technique that fulfils this goal: by genetically engineering cells to contain proteins that make them light-responsive, Miesenböck found he could shine light at the brain and trigger electrical activity in those cells. This technique gave scientists the tools to activate and control specific cell populations in the brain, for the first time. For example, Miesenböck, who directs the Centre for Neural Circuits and Behaviour at the University of Oxford, first used optogenetics to activate courtship responses in fruit flies, and even make headless flies take flight - groundbreaking experiments that allowed him to examine, in unprecedented detail, how neurons drive behaviour.

WIRED talks to Miesenböck, a speaker at WIRED Health 2016, about how optogenetics changed neuroscience, and why intervention holds the key to scientific understanding.

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WIRED: Combining genetics with light - how did that idea come to you?

Gero Miesenböck: There was almost a "eureka" moment. As is often the case, you tend to have your best ideas when you're not trying to have them: suddenly I had this idea - which I must have been incubating for a long time, because I was thinking about manipulating neurons in the brain genetically to emit light so I could visualise their activity. Suddenly I thought, "What if we just turn the thing upside down, and instead of reading activity, write activity using light and genetics?" That was the real breakthrough idea, and then of course came the big challenge of having to make it work.

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Actively "writing" or "creating" brain activity is the principal idea behind optogenetics - how does it work?

Brains are composed of many different kinds of nerve cells, and they are genetically distinct from one another. To deconstruct how the brain works we need to pinpoint the roles these individual classes of cells play in processing information. Optogenetics uses the genetic signatures that define individual cell types to address them selectively in the intact brain - that's the "genetics" component. The "opto" component is to use these genetic signatures to place light-sensitive molecules that are encoded in DNA within these cells. Our brains normally run on electricity, and optogenetics uses those light-sensitive molecules to generate electrical impulses only in the cells that have been genetically targeted to respond to light. Then, it's possible to "talk" to these cells using flashes of light.

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In order to truly understand the brain, you believe we have to intervene. Why is intervention so important?

There was a mathematician called Richard Bellman who said that there's a natural progression in all scientific fields, that people initially start out just observing nature, but as they learn more and more about its underlying forces, scientists change from observers to doers. Being able to do, to control, is important not just for technological reasons; I think it's also the most powerful way to understand how something really works. This is how you can test your hypothesis, how you can find out whether you are actually right or wrong in your understanding.

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If I hypothesise that certain cells have a powerful control over sleep, then my prediction is that if I switch these cells on [using optogenetics on a fruit fly], the fly will fall asleep1. If the experiment doesn't turn out that way then I know my idea is wrong. You can't get the same powerful conclusion by observation. Optogenetics is about connection and control. I think what it enabled in neuroscience - why it has been so impactful, even transformative, perhaps - is that it has moved the field from passive observation to active intervention.

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Optogenetics was first applied to brains, but it has spread...

Yes of course. The heart is one. People have altered the rhythm of a beating heart by using optogenetic interventions. Somebody emailed me a paper a while ago showing that sperm can be controlled optogenetically. And then of course one can interfere not only with electrical but also various aspects of biochemical signalling. One can switch genes on and off, one can turn on and off the chemical messages through which cells communicate. The seed of the idea has now spread to many, many different domains throughout biology.

You use optogenetics to study sleep in fruit flies. Why?

There's a mechanism in the brain that somehow keeps track of how long you've been awake, and puts us to sleep when we have exceeded our limit. Obviously, we don't know what that mechanism responds to. But if we could understand what that is, then I think we'd really break the problem open. We are working on this issue in flies at the moment, and we use optogenetics to control various groups of cells in the brain that either instantly put flies to sleep or wake them up again 2. Then we see how these cell groups normally talk to each other, which signals they send and how they're generated. Being able to understand what normally controls the function of these cells will probably allow us to make significant inroads into discovering the vital but still completely mysterious biological function of sleep.

Is optogenetics driving any interventions that benefit humans right now?

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One example is the visual restoration in the retina. Many people have degeneration of the photoreceptors in their retinas, and optogenetics will provide a simple way of putting some light sensitivity back into them. There are also attempts to develop optogenetic deep-brain stimulation - for example, for treating Parkinson's disease.

What's the future of this technique?

When post-doc candidates write to me and say, "I would like to join your lab to work on optogenetics," I'm always a little disappointed: if you focus on a technology, it will be superseded or outdated or replaced. Or, if it works it's trivial. The great sensation in biology 30 years ago was the polymerase chain reaction. But once it worked, it worked. I think the biological problem must take centre stage, always.

1. "In early experiments we illuminated the whole fly. Now we can control the optical driving signals with much greater precision in space and time."2. Miesenboeck is investigating how quickly fruit flies make decisions. "They think a little hard and longer if we give them a difficult problem to solve."

This article was first published in the July/August 2016 issue of WIRED magazine